Core stabilized microcapsules, method of their preparation and uses thereof

ABSTRACT

The present invention provides core-stabilized microcapsules, wherein said core comprises at least one active agent encapsulated within a metal oxide shell, processes for their preparations, comparisons comprising them and uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 13/500,937, filed onApr. 9, 2017, which is a National Phase application of PCT InternationalApplication No. PCT/IL2010/001092, International Filing Date Dec. 30,2010, claiming priority of U.S. Provisional Patent Application No.61/291,594, filed Dec. 31, 2009, which are hereby incorporated byreference.

FIELD OF THE INVENTION

This invention relates to microcapsules having stabilized core, methodof their preparation and uses thereof.

BACKGROUND OF THE INVENTION

The following publications are considered pertinent for describing thestate of the art in the field of the invention:

-   U.S. Pat. No. 5,500,223-   U.S. Pat. No. 6,303,149-   U.S. Pat. No. 6,238,650-   U.S. Pat. No. 6,468,509-   U.S. Pat. No. 6,436,375-   U.S. Pat. No. 6,337,089-   U.S. Pat. No. 5,891,476-   DE 102004017221-   WO 2008134908-   U.S. Pat. No. 6,270,836-   WO 2008/133482-   WO 2005097056-   S. A. F. Bon et al., Pickering Stabilization as a Tool in the    Fabrication of Complex Nanopatterned Silica Microcapsules, Langmir,    2: 9527-9530, 2007.-   C. A. Prestidge et al. Nanoparticle encapsulation of emulsion    droplets, International Journal of Pharmaceutics 324:92-100, 2006.-   International Journal of Pharmaceutics, vol. 126 (2000) 219-222.-   J. Volkhard et al. J. Microencapsulation, 18(2), 149-152, 2001.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing microcapsuleshaving a core encapsulated within a metal oxide shell, said processcomprising:

-   -   (a) preparing an oil-in-water emulsion by emulsification of an        oily phase comprising at least one active agent and at least one        phase changing material in an aqueous phase, wherein at least        one of said oily phase and aqueous phase comprise a sol-gel        precursor;    -   (b) subjecting said emulsion to microcapsule forming conditions;        thereby obtaining said microcapsules.

In one embodiment of the present invention at least one metal oxidenanoparticle is added to said aqueous phase prior, during or afteremulsification of step (a).

The invention further provides microcapsules obtainable by the processof the invention.

In another one of its aspects the invention provides microcapsulescomprising a core encapsulated by a metal oxide shell, wherein said corehas a viscosity of between about 300 cP to about 1,000,000 cP (whenmeasured under various conditions, for example as will given hereinbelow) and comprises at least one active agent and at least one phasechanging material; wherein the thickness of said metal oxide shell is inthe range 0.1-10 micron; and wherein said shell is obtained from ahydrolyzed and polymerized sol gel precursor. In one embodiment saidcore comprises at least one active agent and at least one phase changingmaterial. In other embodiments said shell of said microcapsules of theinvention is obtained from (a) metal oxide nanoparticles, and (b) ahydrolyzed and polymerized sol gel precursor.

The invention further encompasses a composition comprising microcapsulesof the invention.

In a further aspect the invention provides a method for treating asurface condition in a subject in need thereof, comprising topicallyadministering to said subject a composition of the invention.

The invention further provides a composition comprising microcapsules ofthe invention, for the treatment of a disease, disorder or conditionselected from acne, infection, inflammation, puritis, psoriasis,seborrhea, contact dermatitis, rosacea, and a combination thereof.

In another aspect the invention provides a use of microcapsules of theinvention, for the preparation of a topically administered composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the finding of a process for obtaininga microcapsule having a metal-oxide shell wherein the incorporation ofphase changing material into the core of said microcapsule providesunexpected stability to the encapsulated active agents in the core ofsaid microcapsule.

In some embodiments the present invention a process for obtaining athick and dense coating on a stable water insoluble core, using in someembodiments metal oxide nanoparticles in combination with a sol-gelprecursor, wherein the addition of phase changing material incorporatedinto said core provides further stability parameters to the encapsulatedactive agents and to the pharmaceutical composition comprising them.

Thus, in one aspect of the present invention, there is provided aprocess for preparing microcapsules having a core encapsulated within ametal oxide shell, said process comprising:

-   -   (a) preparing an oil-in-water emulsion by emulsification of an        oily phase comprising at least one active agent and at least one        phase changing material, in an aqueous phase, wherein at least        one of said oily phase and aqueous phase comprise a sol-gel        precursor;    -   (b) subjecting said emulsion to microcapsule forming conditions;        thereby obtaining said microcapsules.

In the present invention the term “core” refers to the inside part ofthe microcapsules comprising at least one active agent and at least onephase changing material that are both surrounded by a metal oxide shellof a microcapsule. It should be noted that additional compounds may bepresent in said core including for example carriers, excipients,pharmaceutically acceptable polymers or salts etc, all in accordancewith the intended use of produced microcapsules, which will be apparentto a skilled artisan preparing said microcapsules. The core of saidmicrocapsule of the invention may comprise said at least one activeagent and at least one phase forming material.

In some embodiments the viscosity of said core at room temperature maybe about 300 cP, 350 cP, 400 cP, 450 cP, 500 cP, 550 cP, 600 cP, 650 cP,700 cP, 750 cP, 800 cP, 900 cP, 1000 cP, 2000 cP, 3000 cP, 4000 cP, 5000cP, 6000 cP, 7000 cP, 8000 cP, 9000 cP, 10,000 cP, 20,000 cP, 30,000 cP,40,000 cP, 50,000 cP, 60,000 cP, 70,000 cP, 80,000 cP, 90,000 cP,100,000 cP, 200,000 cP, 300,000 cP, 400,000 cP, 500,000 cP, 600,000 cP,700,000 cP, 800,000 cP, 900,000 cP or 1,000,000 cP (when measured undervarious conditions). In some embodiments the viscosity of said core atroom temperature is between about 300 to 600 cP. In other embodimentsthe viscosity of said core at room temperature is between about 400 to500 cP. In further embodiments the viscosity of said core at roomtemperature is between about 300 to 10,000 cP. In other embodiments theviscosity of said core at room temperature is between about 5,000 to1,000,000 cP. In some further embodiments the viscosity of said core atroom temperature is between about 20,000 to 1,000,000 cP.

In other embodiments of the invention said core may be solid at roomtemperature. In other embodiments, said core may be in a semi-solidphase at room temperature.

The oily phase utilized by a process of the invention comprises at leastone active agent and at least one phase changing material. Said at leastone active agent may be in a form of a water insoluble liquid ordispersion in water-insoluble liquid comprising said at least one activeagent.

The oily phase may be constituted by a liquid water-insoluble activeagent; which may comprise a first, liquid water-insoluble active agentdissolved and/or dispersed in a second, water insoluble liquid beinganother active agent or serving as a carrier. In another embodiment saidoily phase may comprise a solid active agent dissolved and/or dispersedin a water-insoluble liquid, being another active ingredient or servingas a carrier.

The term “water insoluble liquid” or “dispersion in water-insolubleliquid” refers to a solubility of the liquid (including the ingredientsincluded therein, dissolved and/or dispersed) in water of about lessthan 1% w/w, preferably 0.5% w/w and most preferably 0.15% w/w at roomtemperature (20-25° C.).

Accordingly, the constituents included in the core whether solid orliquid ingredients have a solubility of about less than 1% w/w,preferably 0.5% w/w and most preferably 0.15% w/w at room temperature(20-25° C.). The water insoluble liquid may be for example squalane oil,polydimethylsiloxane, mineral oil, castor oil, aromatic 200, andmixtures thereof.

In the present invention, the term “sol-gel precursor” refers to anymetal or semi-metal organo-metallic monomer, or a prepolymer (whichmeans several monomers polymerized together) thereof, which allows toobtain a glass or ceramic material by in-situ polymerization (aninorganic sol-gel polymerization process). Preferably the sol-gelprecursor is a metal or semi-metal organo-metallic monomer (e.g. a metalor semi-metal alkoxide monomer.

In the present invention, the term “active agent” refers to any moleculeor substance that can be used in medicine or cosmetics and which grantsthe final product (cosmetics, drug, etc.), at least one desiredproperty. In some embodiments one active agent is encapsulated withinsaid microcapsule obtained by the process of the invention. In otherembodiments at least two different active agents are encapsulated withinsaid microcapsule obtained by the process of the invention. In otherembodiments said at least two different active agents are eachencapsulated within a separate microcapsule, obtained eitherindependently or simultaneously by the process of the invention.

As used herein the term “metal oxide nanoparticles” refers tosubstantially pure metal oxide nanoparticles consisting essentially ofor comprised wholly of metal oxide. In some embodiments metal oxidenanoparticles do not include organic material, in particular notpolystyrene.

The term “phase changing material” (PCM) is meant to encompass anysubstance capable of changing its state of matter (phase), or at leastits viscosity, in accordance with the temperature it is exposed to. PCMstypically have a high heat of fusion which enables them to melt andsolidify at certain temperatures, and are capable of storing andreleasing large amounts of energy. Heat is absorbed or released when thePCM material changes from solid to liquid and vice versa. When PCMsreach the temperature at which they change phase or viscosity (forexample their melting temperature), they absorb large amounts of heat atan almost constant temperature. The PCM continues to absorb heat withouta significant raise in temperature until all the material is transformedto the liquid phase. When the ambient temperature around a liquidmaterial falls, the PCM solidifies, releasing its stored latent heat. Inaccordance with an embodiment of the present invention a phase changingmaterial utilized by a process of the invention is an organic material,which is non-reactive with any compound utilized by a process of theinvention and is characterized by the fact that at room temperature saidPCM has a viscosity of between about 300 cP to 1,000,000 cP (whenmeasured under various conditions). In some embodiments the viscosity ofsaid PCM at room temperature may be 300 cP, 350 cP, 400 cP, 450 cP, 500cP, 550 cP, 600 cP, 650 cP, 700 cP, 750 cP, 800 cP, 900 cP, 1000 cP,2000 cP, 3000 cP, 4000 cP, 5000 cP, 6000 cP, 7000 cP, 8000 cP, 9000 cP,10,000 cP, 20,000 cP, 30,000 cP, 40,000 cP, 50,000 cP, 60,000 cP, 70,000cP, 80,000 cP, 90,000 cP, 100,000 cP, 200,000 cP, 300,000 cP, 400,000cP, 500,000 cP, 600,000 cP, 700,000 cP, 800,000 cP, 900,000 cP or1,000,000 cP (when measured under various conditions).

In one embodiment, said at least one phase changing material is selectedfrom natural or synthetic paraffins (e.g. having a molecular formula ofC_(n)H_(2n+2), wherein n=10-100), C₁₀-C₁₀₀ alkane, C₁₀-C₁₀₀ alkene(having at least one double bond), C₁₀-C₁₀₀ alkyne (having at least onetriple bond), aliphatic alcohols (e.g. having a molecular formula ofCH₃(CH₂)_(n)OH n=10-100) and fatty acids (e.g. having a molecularformula of CH₃(CH₂)_(2n)COOH n=10-100), or any combination thereof.

In some embodiments said at least one phase changing material is atleast one natural or synthetic paraffin. In some embodiments said atleast one phase changing material is a C₁₀-C₁₀₀ aliphatic alcohol (inother embodiments C₁₀, C₂₀, C₃₀, C₄₀, C₅₀, C₆₀, C₇₀, C₈₀, C₉₀ to C₁₀₀aliphatic alcohol). In further embodiments said at least one phasechanging material is a C₁₀-C₁₀₀ aliphatic fatty acid (in otherembodiments C₁₀, C₂₀, C₃₀, C₄₀, C₅₀, C₆₀, C₇₀, C₈₀, C₉₀ to C₁₀₀aliphatic fatty acid).

In one embodiment said PCMs are liqudified (or at least becomesubstantially or partially liquidified, pleable or semi-solid, andcapable of being handled by a process of the invention) at a temperaturerange of between about 35° C. to about 60° C., more preferably in atemperature range of between about 35° C. to about 45° C.

Examples of phase changing materials capable of being used by theprocesses of the invention include, but are not limited to: Carnauba wax(m.p. 82-86° C.), Beeswax pure (m.p. 61-65° C.), Beeswax white pure,(m.p. 61-65° C.), Beeswax bleached technical (m.p. 61-65° C.), Montanwax bleached (m.p. 80-86° C.), Montan wax bleached, partially saponified(m.p. 99-105° C.), Montanic acid (m.p. 81-87° C.), Hydrocarbon waxsynthetic (m.p. 106-114° C.), Microcrystalline wax (m.p. 89-95° C.),Microcrystalline wax (m.p. 76-82° C.), Hardwax partially saponified(m.p. 104-109° C.), Beeswax yellow (m.p. 61-66° C.), Polishing Wax (m.p.78-84° C.), Castor wax (m.p. 83-89° C.), Microwax (m.p. 89-95° C.),Microwax (m.p. 80-86° C.), Microwax (m.p. 76-82° C.), Ozokerite (m.p.72-79° C.), Microcrystalline wax, plastic (m.p. 76-82° C.),Microcrystalline wax, soft (m.p. 74-80° C.), Wax blend (m.p. 62-68° C.),Polyolefin wax (m.p. 65-75° C.), Lanolin, Shellac, Bayberry wax (m.p.45° C.), Candelilla wax (m.p. 67-79° C.), Ouricury wax, Rice bran wax(m.p. 77-86° C.), Soy candle (wax), Paraffin (m.p. 47-64° C.), Chinesewax, and any combinations thereof.

In one embodiment of a process of the invention, said at least one phasechanging material is in a liquid state. Thus, prior to the addition ofsaid at least one PCM, its temperature is raised until it issubstantially homogenously liquidified. In a further embodiment of thepresent invention, a process of the invention is carried out under atemperature wherein said at least one phase changing material is in aliquid state, throughout the entire emulsification and encapsulationprocess disclosed herein above and below. It is noted that said at leastone PCM utilized by a process of the present invention, is selected suchthat its heat of fusion allows for processes of the invention to becarried out substantially without compromising the active agents used,the emulsion formed and the metal oxide shell produced for themicrocapsules of the invention.

In one embodiment of the present invention at least one metal oxidenanoparticle is added to said aqueous phase prior, during or afteremulsification of step (a).

In a further embodiment of a process of the invention, the processfurther comprises a step of cooling obtained microcapsules to roomtemperature. It is noted that upon cooling of said obtainedmicrocapsules, the viscosity of said core, comprising said at least oneactive agent and at least one PCM, changes to have values of betweenabout 300 cP to 1,000,000 cP (when measured under various conditions).It should be understood that such PCMs used by a process of theinvention are accumulated in the core of obtained microcapsules and arenot incorporated in any part of the metal-oxide shell formed byencapsulation process of the invention.

It is further noted that such microcapsules obtained by a process of theinvention, demonstrate a higher stability, as measured in the amount ofleakage measured upon long term storage of said microcapsules.

In some embodiments of the invention, microcapsules obtained by aprocess of the invention are stable for a period of at least 2 weeks atroom temperature. In some embodiments of the invention, microcapsulesobtained by a process of the invention are stable for a period of atleast 2 months at room temperature. In some embodiments of theinvention, microcapsules obtained by a process of the invention arestable for a period of between about 2 weeks to 2 years at roomtemperature. In other embodiments microcapsules obtained by a process ofthe invention are stable for a period of between about 2 months to about2 years at room temperature. In this context it should be noted that astability of a microcapsule of the invention, obtained by a process ofthe invention is measured by the ability of said microcapsule tosubstantially maintain said at least one active agent within saidmicrocapsule, with a maximal leakage of between about 0 to 5% of saidactive agent, for a set period of time under conditions of temperatureand RH specified.

In a further embodiment of a process of the invention, saidmicrocapsules encapsulating said at least one active agent and at leastone phase changing material have a viscosity of between about 300 cP toabout 1,000,000 cP.

According to an embodiment of the present invention said core comprisesa pharmaceutical agent, cosmetic agent, or agrochemical agent.

Additionally according to an embodiment of the present invention saidcore comprises a dermatological agent.

Further according to an embodiment of the present invention saiddermatological agent is selected from anti-fungal agents, anti-bacterialagents, anti-inflammatory agents, anti-puritic agents, anti-psoriaticagents, anti-acne agents, anti-rosacea agents, and any combinationsthereof.

In some embodiments, an anti-acne agent is selected from benzoylperoxide, retinoid, and mixtures thereof. The retinoid may be forexample tretinoin (all trans retinoic acid, ATRA), tazarotene,iso-tretinoin, adapalene or mixtures thereof.

According to an embodiment of the present invention said metal oxidenanoparticles are selected from Silica, Titania, Zirconia, ZnO, and anymixtures thereof.

According to another embodiment of the present invention said metaloxide nanoparticles have a particle size diameter (d50) in the range of1-100 nm. In other embodiments particle size diameter (d50) is in therange of 1-50 nm, more preferably 5-30 nm.

By the term “particle size diameter (d50) in the range of 1-100nanometer” is meant to encompass particles of which at least 50% byvolume have diameters in the range of 1-100 nanometer.

Unless otherwise indicated, the nanoparticle size will be given usingthe D₉₀ value, i.e. the size of at least 90% of said particles (measuredby volume). Thus, for example, when referring to nanoparticles having adiameter of at least about 10 nm, it should be understood to mean thatthe D₉₀ value of said nanoparticles is 10 nanometer. D₉₀ values may bemeasured by laser diffraction.

According to another embodiment, a process of the present inventionfurther comprising adding at least one metal oxide salt to said aqueousphase either prior, during or after emulsification in step (a). Inanother embodiment said metal oxide salt is selected from sodiumsilicate, potassium silicate, sodium titanate, potassium titanate,sodium zirconate, potassium zirconate, and mixtures thereof. In anotherembodiment the weight ratio between metal oxide nanoparticles and metaloxide salt is in the range 99:1 to 1:2, preferably 50:1 to 2:1, morepreferably 50:1 to 10:1.

According to an embodiment the process of the present invention furthercomprising adding a binding or cross-linking additive selected from apolymeric agent, a di- or tri-valent metal salt, a polyelectrolyte, andmixtures thereof, to said aqueous phase either prior, during or afteremulsification of step (a). It is noted that when using these type ofbinding or cross-linking additive the prepared microcapsules will have amore cross-linked and stronger metal oxide shell.

In one embodiment, said polymeric agent is selected from sodiumalginate, polyvinyl alcohol, carboxymethyl cellulose, polyvinylpyrrolidone, and mixtures thereof.

In another embodiment, said di- or tri-valent metal salt is selectedfrom aluminum sulfate, sodium aluminate, sodium borate, calciumchloride, and mixtures thereof.

Without being bound to theory the binding or cross-linking additives mayprovide such strengthening and cross-linking properties of microcapsulesshell as follows:

Aluminum sulfate—the positively charged aluminum cations may beattracted to the negatively charged metal oxide nanoparticles and assuch may work as cross-linkers between the metal oxide nanoparticleswhich are adsorbed on the oil droplet-water interface

Sodium aluminate—sodium aluminate may react with the silanol groups onthe metal oxide nanoparticles surface, and as such may work ascross-linkers between the metal oxide nanoparticles which are adsorbedon the oil droplet-water interface.

PVA (polyvivyl alcohol) may adsorb onto the metal oxide shell viahydrogen bonds and also can be cross-linked by sodium borate.

Sodium borate—sodium borate may cross-link the PVA with the metal oxideshell of the microcapsules.

Sodium alginate—sodium alginate may adsorb onto the metal oxide shell(produced from adsorption of metal oxide nanoparticles) and may becross-linked by addition of calcium chloride.

PDAC 7 (polyquaternium 7)—PDAC 7 may be used for coating of the metaloxide shell. PDAC 7 which is positively charged may adsorb onto thenegatively charged metal oxide shell and as such decrease the “gaps”between the metal oxide nanopartices and thus strengthen the shell.

CMC (carboxymethyl cellulose)—CMC may be used for additional coating ofthe metal oxide shell. It can be used after coatings with PDAC 7.

In one embodiment, said polyelectrolyte is selected fromPolyquaternium-7 (Dimethyldiallylammonium chloride acrylamidecopolymer), Polyquaternium-1 [Poly[(dimethyliminio)-2-butene-1,4-diylchloride],α-[4-[tris(2-hydroxyethyl)ammonio]-2-butenyl]-ω-[tris(2-hydroxyethyl)ammonio]-,dichloride], Polyquaternium-10 [Cellulose 2-hydroxyethyl2-(2-hydroxy-3-(trimethylammonio)propoxy)ethyl-2-hydroxy-3-(trimethylammonio)propylether, chloride], Chitosan, Polylysine, and mixtures thereof.

According to one embodiment at least one of said oily and aqueous phasescomprise at least one surfactant. In one embodiment said surfactant isselected from a cationic surfactant, an anionic surfactant, a non-ionicsurfactant and mixtures thereof. In one embodiment the at least onesurfactant is a cationic surfactant. In a further embodiment said atleast one cationic surfactant is cetyltrimethyl ammonium chloride(CTAC).

In another embodiment said oily phase may comprise a hydrophobicsurfactant, hydrophobic polymeric surfactant, or mixtures thereof. Inone embodiment the hydrophobic surfactant or hydrophobic polymericsurfactant is a non-ionic surfactant. The hydrophilic surfactant may befor example an anionic, a cationic, a non-ionic surfactant, or mixturesthereof.

In some embodiments the concentration of the cationic surfactant in theaqueous phase may be from 0.1 to 5% (w/w), in other embodiments from 1to 5% (w/w). It is appreciated that the concentration of the surfactantwill also depend on the percentage of the oily phase and aqueous phase.In some embodiments the concentration of the surfactant may be 5-10%(w/w) from the weight of the oily phase.

According to another embodiment of the present invention said oily phasecomprises a sol-gel precursor.

According to a further embodiment of the present invention said sol-gelprecursors are selected from metal alkoxide monomers, semi-metalalkoxide monomers, metal ester monomers, semi-metal ester monomers andfrom monomers of the formula M(R)_(n)(P)_(m), wherein M is a metallic orsemi metallic element, R is a hydrolysable substituent, n is an integerfrom 2 to 6, P is a non polymerizable substituent and m is and integerfrom 0 to 6, a partially hydrolyzed and partially condensed polymer ofany of the above, and mixtures of any of the above. In one embodiment,said metallic or semi metallic element is selected from Si, Ti, Zr, Al,and Zn.

In another embodiment, said sol-gel precursors are selected from siliconalkoxide monomers, silicon ester monomers, monomers of the formulaSi(R)_(n)(P)_(m), wherein R is a hydrolysable substituent, n is aninteger from 2 to 4, P is a non polymerizable substituent and m is aninteger from 0 to 4, a partially hydrolyzed and partially condensedpolymer of any of the above, and mixtures of any of the above. In oneembodiment, said silicon alkoxide monomer is selected from tetramethoxysilane, tetraethoxy silane, and mixtures thereof. In a furtherembodiment, said monomers of the formula Si(R)_(n)(P)_(m) are selectedfrom methyl trimethoxysilane, dimethyl dimethoxysilane, and mixturesthereof. In yet a further embodiment, said sol-gel precursor is amonomer (e.g. a metal alkoxide monomer, a semi-metal alkoxide monomer)as described hereinbefore.

According to an embodiment of the present invention the pH of saidaqueous phase is in the range 2-9. In another embodiment, the pH of saidaqueous phase is in the range 2-7, even more preferably the pH is in therange 3-5.

According to an embodiment of the present invention said microcapsuleforming conditions comprise isolating the microcapsules throughprocedures selected from at least one of: separation by centrifuge,filtration, evaporation, re-suspension in aqueous medium, and dialysis.

In another embodiment of the present invention said microcapsulesforming conditions comprise altering the pH of the formed emulsion to arange of between about 2 to about 9, preferably the pH is in the range3-5.

According to another embodiment of the present invention saidmicrocapsule forming conditions comprise stirring of said emulsion. Insome embodiments said stirring may be for example by mechanical stirrerat 200-500 rpm.

According to another embodiment of the present invention saidmicrocapsule forming conditions comprise drying the obtainedmicrocapsules in suspension.

According to another embodiment the product obtained by a process of theinvention is a suspension of said formed microcapsules.

According to a further embodiment of the present invention the productobtained by a process of the invention is a powder of saidmicrocapsules.

In another aspect of the present invention there is providedmicrocapsules obtainable by the process of the present invention.

Yet in another aspect of the present invention there is providedmicrocapsules comprising a core encapsulated by a metal oxide shell,wherein said core has a viscosity of between about 300 cP to about1,000,000 cP (when measured under various conditions); wherein thethickness of said metal oxide shell is in the range 0.1-10 micron; andwherein said shell is obtained from (a) metal oxide nanoparticles, and(b) a hydrolyzed and polymerized sol gel precursor.

In some embodiments the viscosity of said core at room temperature maybe 350 cP, 400 cP, 450 cP, 500 cP, 550 cP, 600 cP, 650 cP, 700 cP, 750cP, 800 cP, 900 cP, 1000 cP, 2000 cP, 3000 cP, 4000 cP, 5000 cP, 6000cP, 7000 cP, 8000 cP, 9000 cP, 10,000 cP, 20,000 cP, 30,000 cP, 40,000cP, 50,000 cP, 60,000 cP, 70,000 cP, 80,000 cP, 90,000 cP, 100,000 cP,200,000 cP, 300,000 cP, 400,000 cP, 500,000 cP, 600,000 cP, 700,000 cP,800,000 cP, 900,000 cP or 1,000,000 cP (when measured under variousconditions).

It is noted that viscosity value measurement depends on the instrumentof measurement, spindle used, speed and temperature of measurement.Unless otherwise mentioned the viscosity measurements given in thepresent invention were measured using a Brookfield LVDV-II+Proviscometer equipped with a small sample adaptor, spindle #21 at 6 RPMand temperature of 30° C.

In some embodiments, a microcapsule of the invention is capable of beingstable (i.e. maintain at least about 0 to 5% of said encapsulated atleast one active agent) for a period of between about 2 weeks to about 2years at room temperature. In other embodiments, a microcapsule of theinvention is capable of being stable for a period of between aboutmonths to about 2 years at room temperature. In other embodiments, amicrocapsule of the invention is capable of being stable for a period ofat least 2 weeks at room temperature. In further embodiments, amicrocapsule of the invention is capable of being stable for a period ofat least 2 months at room temperature.

Further according to another embodiment of the invention the metal oxideshell has a width (thickness) of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 1, 1.5, 2 or 5 micron or above, preferably up to 10 micron.The core, shell, etc. constituents may be as described in the presentinvention.

The width of the metal oxide layer may be determined for example by aTransmission Electron Microscope or Confocal Microscope such that in acircular cross sectional area of the microcapsules the smallest width isat least e.g. 0.1 micron (the width is determined as the smallestdistance from the outer surface of the microcapsules (i.e. metal oxidesurface) to the core-metal oxide interface).

In another aspect of the present invention there is provided acomposition comprising microcapsules of the present invention.

Further in another aspect of the present invention there is provided amethod for treating a surface condition in a subject in need thereof,comprising topically administering to said subject a composition of thepresent invention, wherein the core material comprises a dermatologicalagent.

The term “treating” or “treatment” as used herein includes any treatmentof a condition, disease or disorder associated with a patient's bodysurface such as the skin or mucosal membrane, and includes inhibitingthe disease or disorder (i.e. arresting its development), relieving thedisease or disorder (i.e. causing regression of the disease ordisorder), or relieving the conditions caused by the disease (i.e.symptoms of the disease). The concentrations of the dermatologicalagents that can be used for treatment of a specific disease or disordermay be as described in The Merck index an encyclopedia of chemical drugsand biologicals, Rahway, N.J.; Merck & Co; 1989, incorporated herein byreference in its entirety.

Although individual needs may vary, determination of optimal ranges foreffective amounts of the compositions is within the skill of the art.Generally, the dosage required to provide an effective amount of apharmaceutical composition, which can be adjusted by one skilled in theart, will vary depending on the age, health, physical condition, weight,type and extent of the disease or disorder of the recipient, frequencyof treatment, the nature of concurrent therapy (if any) and the natureand scope of the desired effect(s).

When referring to pharmaceutical compositions comprising a compound ofthe subject invention it should be understood to encompass admixtures ofmicrocapsules of the invention, with pharmaceutically acceptableauxiliaries, and optionally other therapeutic agents. The auxiliariesmust be “acceptable” in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientsthereof.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintrathecal) administration or administration via an implant. Thecompositions may be prepared by any method well known in the art ofpharmacy. Such methods include the step of bringing in associationcompounds used in the invention or combinations thereof with anyauxiliary agent.

Auxiliary agent(s), also named accessory ingredient(s), include thoseconventional in the art, such as carriers, fillers, binders, diluents,disintegrants, lubricants, colorants, flavouring agents, anti-oxidants,and wetting agents.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets, dragées orcapsules, or as a powder or granules, or as a solution or suspension.The composition may also be presented as a bolus or paste. Thecompositions can further be processed into a suppository or enema forrectal administration.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material,including instructions for the use of the composition for a use ashereinbefore described.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile injections. The compositions may be presented inunit-dose or multi-dose containers, for example sealed vials andampoules, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of sterile liquid carrier, for examplewater, prior to use.

For transdermal administration, e.g. gels, patches or sprays can becontemplated. Compositions or formulations suitable for pulmonaryadministration e.g. by nasal inhalation include fine dusts or mistswhich may be generated by means of metered dose pressurized aerosols,nebulisers or insufflators.

The exact dose and regimen of administration of the composition willnecessarily be dependent upon the therapeutic or nutritional effect tobe achieved and may vary with the particular formula, the route ofadministration, and the age and condition of the individual subject towhom the composition is to be administered.

According to an embodiment of the present invention said surface is skinor mucosal membrane.

According to another embodiment of the present invention said surfacecondition is a skin disease or disorder selected from acne, infection,inflammation, puritis, psoriasis, seborrhea, contact dermatitis,rosacea, and a combination thereof.

Additionally, in another aspect of the present invention there isprovided a composition comprising microcapsules as described in thepresent invention, wherein the core comprises a dermatological agent,for treatment of a disease or disorder selected from acne, infection,inflammation, puritis, psoriasis, seborrhea, contact dermatitis,rosacea, and a combination thereof.

Yet, in another aspect there is provided a use of the microcapsules ofthe present invention, wherein said core comprises a dermatologicalagent for the preparation of a topically administered composition.

According to an embodiment of the invention said topical administrationis for treating a disease or disorder selected from acne, psoriasis,seborrhea, contact dermatitis, infection, rosacea, inflammation, and acombination thereof.

In another aspect of the present invention there is provided acomposition for pest control comprising the microcapsules of theinvention, wherein said core comprises a pesticide. In one embodiment ofthe present invention said pesticide is selected from a herbicide, aninsecticide, a fungicide, and mixtures thereof.

According to yet another embodiment of the present invention saidcomposition is for use in crop protection or non-crop pest control.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The following Examples are representative of techniques employed by theinventors in carrying out aspects of the present invention. It should beappreciated that while these techniques are exemplary of preferredembodiments for the practice of the invention, those of skill in theart, in light of the present disclosure, will recognize that numerousmodifications can be made without departing from the spirit and intendedscope of the invention.

Unless otherwise indicated “%” refers to weight per weight (w/w) %.

“BPO (75%)” refers to 75% w/w BPO (Benzoyl peroxide) with 25% w/w water.

“Ludox® TM 50 (50%)” refers to a dispersion of silica nanoparticles(average particle size diameter of about 20-30 nm) in water (50% w/w inwater). Ludox TM 50 was obtained from Sigma-Aldrich, Israel.

“Ludox® AM-30” refers to colloidal silica stabilized with sodiumaluminate and dispersed in water (30% w/w in water).

Ludox® AM-30 was obtained from Sigma-Aldrich, Israel.

“CTAC (29%)” refers to a solution of cetyl trimethyl ammonium chloride29% w/w in water.

“PVA (10%)” refers to a solution of polyvinyl alcohol 10% w/w in water.

“sodium silicate (25%)” refers to a solution of sodium silicate 25% w/win water.

“GMIS” refers to glyceryl monoisostearate. GMIS was obtained from ScherChemicals, USA.

“aluminum sulfate solution (50%)” or “aluminum sulfate (50%)” refers toa solution of aluminum sulfate decaoctahydrate 50% w/w in water.

“PDAC 7 (5%)” refers to a solution of polyquaternium 7(Diallyldimethylammonium chloride/acrylamide copolymer), 5% w/w inwater.

“CMC (10%)” refers to a solution of sodium salt of carboxymethylcellulose 10% w/w in water.

“sodium aluminate (50%)” refers to solution of sodium aluminate 50% w/win water.

“sodium borate (5%)” refers to solution of sodium borate 5% w/w inwater.

“sodium alginate (5%)” refers to solution of sodium alginate 5% w/w inwater.

“Beeswax” refers to Beeswax pure (m.p. 61-65° C.), Beeswax white pure,(m.p. 61-65° C.), Beeswax bleached technical (m.p. 61-65° C.).

“PVP K30 (40%)” refers to solution of PVP K30 (PolyvinylpyrrolidoneK-30) 40% w/w in water.

EXAMPLES Example 1: Encapsulation Process ATRA (E-ATRA) Core-Shell Step

-   -   1. Aqueous phase (phase A): 2.53 g CTAC (30.7%) and 386.27 g WFI        were stirred with a magnetic stirrer to homogeneity.    -   2. Beeswax ingredient: 30.0 g Beeswax, heated to 70° C. until        Beeswax was liquid.    -   3. Oil phase: 90.0 g TEOS, and 97.01 g Squalane were stirred        with a magnetic stirrer to dissolution. 30.0 g ATRA were added        to solution and stirred, using same magnetic stirrer, for        additional 10 min and milled in Dynomill at 5000 rpm for 10 min.        Milled oil phase was heated to 55° C. under magnetic stirring,        using a water bath.    -   4. Aqueous phase was heated to 55° C. under magnetic stirring,        using a water bath.    -   5. In a IL beaker, 91.37 g milled oil phase and 5.83 g Beeswax,        were mixed for 5 minutes at 55° C. under magnetic stirring,        using a water bath (phase B).    -   6. Phase C: 14.0 g Sodium silicate solution (25%) and 30.0 g HCl        5N.    -   7. Phase B mixed under high shear mixing at 4000 rpm (Polytron        6100).    -   8. Phase A was added to Phase B, and mixed with high shear at        4000 rpm for 1 min. after which high shear speed was reduced to        3000 rpm.    -   9. Phase C was added until pH 7.0±0.2 was reached.    -   10. HCl 5N was added to emulsion until pH 3.0±0.2 was reached.    -   11. Emulsion was mixed with high shear for additional 2 min at        3000 rpm.    -   12. Emulsion was stir for 17 hr. at 50° C. at 80 rpm and then        cool to 25° C. until core-shell suspension was achieved.

Coating Step (Optional)

-   -   13. 150.0 g of core-shell suspension was placed under high-shear        at 2500 rpm.    -   14. 5% NaOH 5N were added until pH 5.0+0.2.    -   15. 1.2 g PDAC-7 (3%) was added and mixture was stirred for 1        min.    -   16. 1.2 g Sodium silicate (25%) was added and pH adjusted to        5.0+0.2 with HCl 5N solution, and mixture was stirred for 1 min.        (1st cycle).    -   17. Coating cycle (steps 15-16) was repeated at least 10 times.

The viscosity of the core of the obtained microcapsules was measured tobe between 475 to 565 cP (as measured using a Brookfield LVDV-II+Proviscometer equipped with a small sample adaptor, spindle #21 at 6 RPMand temperature of 30° C.).

Example 2—Encapsulation of BPO (Benzoyl Peroxide) (BPO Dispersed inDC-246)

a) Preparing the Oil Phase:

-   -   A mixture of 67.68 g BPO (75%), 132.04 g DC-246        (cyclohexasiloxane, Dow Cornig, USA) and 10.06 g Span 65 as        dispersant agent and 45.6 g of TEOS (tetraethoxy silane) were        milled first by high shear at 4000 rpm for 2 minutes and then by        microfluidizer for 15 minutes.

b) Preparing the Water Phase:

-   -   An aqueous phase including 6.06 g of Myrj 45        (polyoxyethylene (8) stearate), 2.68 g CTAC (29%), 64.54 g PVA        (10%) and 328.13 g of water was prepared.

The oil phase (a) was added to the water phase (b) under shearing at6000 rpm for 2 minutes. Then, 49.93 g of Ludox® TM 50 (50%) and 5 ml ofsodium silicate (25%) were added, and then the pH was adjusted to 3. Themixture was transferred to reactor and stirred for 20 h.

Example 3—Encapsulation of BPO (BPO Dispersed in DC-350)

a) Preparing the Oil Phase:

-   -   A mixture of 67.49 g BPO (75%), 130.92 g DC-350        (polydimethylsiloxane, obtained from Dow coming, USA) and 10.16        g cetyl alcohol as dispersant agent and 45.42 g of TEOS were        milled first by high shear at 4000 rpm for 2 minutes and then by        microfluidizer for 15 minutes.

b) Preparing the Water Phase:

-   -   A water phase including 5.69 g of Myrj 45 (polyoxyethylene (8)        stearate), 2.25 g CTAC (29%), 65.05 g PVA (10%) and 327.24 g of        water, was prepared.

The two phases were preheated at 50° C. and then the oil phase (a) wasadded to the water phase (b) under shearing at 5000 rpm for 2 minutes.Then, 50.09 g of Ludox® TM 50 (50%) were added and the solution becameviscous. Then, 5 ml of sodium silicate (25%) was diluted up to 100.09 gwith water and the resulted solution was added to the viscous mixtureunder shearing of 5000 rpm for 1 minute. The pH was adjusted to 3 andthen the mixture was transferred to reactor and stirred for 20 h.

Example 4—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 68.64 g BPO (75%), 129.58 g squalane (obtained fron        from Lake Oil, Spain) and 5.08 g GMIS as dispersant agent and        89.85 g of TEOS were milled first by high shear at 10000 rpm for        2 minutes and then by microfluidizer for 15 minutes.

b) Preparing the Water Phase:

-   -   A water phase including 1.18 g CTAC (29%), 65.10 g PVA (10%) and        329.93 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at5000 rpm for 30 seconds. Then, 49.64 g of Ludox® TM 50 (50%) was addedand shearing continued further 30 seconds. Then, 20.72 g of aluminumsulfate solution (50%) were added and the obtained pH was 3. The mixturewas transferred to reactor preheated at 40° C. and the mixture wasstirred at 118 rpm for 4 hours. Then, the temperature was decreased toroom temperature and stirring continued for 20 h.

Example 5—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 80.63 g BPO (75%), 108.15 g squalane (obtained fron        from Lake Oil, Spain) and 5.71 g GMIS as dispersant agent and        27.97 g of TEOS were milled first by high shear at 10000 rpm for        1 minute and then by microfluidizer for 15 minutes.

b) Preparing the Water Phase:

-   -   A water phase including 1.02 g CTAC (29%), 60.27 g PVA (10%) and        290.09 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at5000 rpm for 30 seconds. Then, 30.58 g of Ludox® TM 50 (50%) was addedand shearing continued further 30 seconds. Then, 20.09 g of aluminumsulfate solution (50%) were added under shearing for 30 seconds and theobtained pH was 3.2. The mixture was transferred to reactor preheated at40° C. and the mixture was stirred at 100 rpm for 4 hours. Then, thetemperature was decreased to room temperature and stirring continued for20 h.

Example 6—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 53.19 g BPO (75%), 75.21 g squalane and 5.12 g GMIS        as dispersant agent and 80.68 g of TEOS were milled first by        high shear at 10000 rpm for 1 minute and then by microfluidizer        for 15 minutes.

b) Preparing the Water Phase:

-   -   A water phase including 4.16 g CTAC (29%), 6.5 g PVA (10%) and        280.45 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at5000 rpm for 30 seconds. Then, 90.11 g of Ludox® TM 50 (50%) was addedand shearing continued further 30 seconds. Then, 9.96 g of aluminumsulfate dissolved in 15.19 g water were added and the resulted mixturewas milled at 6100 rpm for 1 minute. The mixture was then transferred toreactor preheated at 38.8° C. and it was stirred at 118 rpm for 4 hours.Then, the temperature was decreased to room temperature and stirringcontinued for 20 h.

Example 7—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 106.35 g BPO (75%), 88.09 g squalane and 4.91 g        GMIS as dispersant agent and 41.05 g of TEOS were milled first        by high shear at 10000 rpm for 1 minute. A thick mixture was        obtained and it could not be milled by microfluidizer.

b) Preparing the Water Phase:

-   -   A water phase including 1.31 g CTAC (29%), 6.3 g PVA (10%) and        283.1 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at5000 rpm for 30 seconds. Then, 60.66 g of Ludox® TM 50 (50%) was addedand shearing continued further 30 seconds. Then, 50.18 g of aluminumsulfate (50%) were added and the resulted mixture was milled at 6000 rpmfor 1 minute. The mixture was then transferred to reactor preheated at41.8° C. and it was stirred at 100 rpm for 4 hours. Then, thetemperature was cooled down to room temperature and stirring continuedfor 20 h.

Example 8—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 106.24 g BPO (75%), 61.12 g squalane and 5.65 g        cetyl alcohol as dispersant agent and 60.49 g of TEOS were        milled first by high shear at 10000 rpm for 1.5 minutes. A thick        mixture was obtained and it could not be milled by        microfluidizer.

b) Preparing the Water Phase:

-   -   A water phase including 1.09 g CTAC (29%), 61.52 g PVA (10%) and        269.45 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at5000 rpm for 30 seconds. Then, 59.87 g of Ludox® TM 50 (50%) was addedand shearing continued further 1 minute. Then, 21.87 g of aluminumsulfate (50%) were added and the resulted mixture was milled at 6000 rpmfor 1 minute. The mixture was then transferred to reactor preheated at40° C. and stirred for 4 hours. Then, the temperature was cooled down toroom temperature and stirring continued for 20 h.

Example 9—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 105.28 g BPO (75%), 130.13 g squalane and 5.48 g        Span 20 and 32.51 g of TEOS were milled first by high shear at        10000 rpm for 1 minute. A thick mixture was obtained and it        could not be milled by microfluidizer.

b) Preparing the Water Phase:

-   -   An aqueous phase including 4.31 g CTAC (29%), 6.5 g PVA (10%)        and 279.8 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at4000 rpm and then 90.41 g of Ludox® TM 50 (50%) was added and shearingcontinued 1 minute. Then, 20.88 g of aluminum sulfate (50%) were addedand the resulted mixture was milled at 5000 rpm for 1 minute. Themixture was then transferred to reactor preheated at 39.2° C. andstirred at 103 rpm for 4 hours. Then, the temperature was cooled down toroom temperature and stirring continued for 60 h.

Example 10—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 80.25 g BPO (75%), 107.04 g squalane and 5.01 g        cetyl alcohol and 30.40 g of TEOS were milled first by high        shear at 10000 rpm for 1 minute. A thick mixture was obtained        and it could not be milled by microfluidizer.

b) Preparing the Water Phase:

-   -   A water phase including 4.33 g CTAC (29%), 6.16 g PVA (10%) and        279.59 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at4000 rpm and then 59.43 g of Ludox® TM 50 (50%) was added, and then theresulted mixture was homogenized at 8000 rpm for 1 minute since themixture was very thick. Then, 49.45 g of aluminum sulfate (50%) wereadded and the resulted mixture was milled at 8000 rpm for 30 seconds.The mixture was then transferred to reactor preheated at 41.2° C. andstirred at 103 rpm for 4 hours. Then, the temperature was cooled down toroom temperature and stirring continued for 20 h.

Example 11—Encapsulation of BPO (BPO Dispersed in Squalane)

a) Preparing the Oil Phase:

-   -   A mixture of 80.2 g BPO (75%), 93.5 g squalane (obtained from        Lake Oil, Spain) and 5.38 g Span 20 and 42.07 g of TEOS were        milled first by high shear at 10000 rpm for 1 minute and then by        microfluidizer for 15 minutes.

b) Preparing the Water Phase:

-   -   A water phase including 4.05 g CTAC (29%), 61.51 g PVA (10%) and        257.74 g of water, was prepared.

The oil phase (a) was added to the water phase (b) under shearing at4000 rpm and then 61.42 g of Ludox® TM 50 (50%) was added and shearingat 5000 rpm continued for 1 minute. Then, 21.1 g of aluminum sulfate(50%) were added and the resulted mixture was milled at 5000 rpm for 1minute. The mixture was then transferred to reactor preheated at 41.2°C. and stirred at 103 rpm for 4 hours. Then, the temperature was cooleddown to room temperature and stirring continued for 20 h.

Example 12—Formulation of Encapsulated ATRA and Encapsulated BPO (E-ATRA0.1%/E-BPO 6%)

Ingredients:

-   -   (a) E-ATRA suspension: equivalent to 0.1% ATRA, (prepared        according to the procedure in Example 1).    -   (b) E-BPO suspension: equivalent to 6%0 BPO (prepared according        to the procedure in any one of Examples 2-11).    -   (c) Carbomer 980: 1.2% (Carbopol® 980 NF from Lubrizol)    -   (d) Carbomer 1342: 0.3% (Pemulen TR-2 NF from Lubrizol)    -   (e) Sodium hydroxide (Sodium hydroxide pellets extra pure Ph        Eur, BP, JP, NF, FCC, E 524 from Merck)    -   (f) Water

Formulation Preparation:

Carbomer 980 & carbomer 1342 were dispersed in water to a lump-free,homogeneous suspension. E-ATRA suspension was added into the carbomerssuspension. E-BPO suspension was added into the carbomers suspension.Sodium hydroxide was added to achieve pH values of 5.0±0.1. Water wasadded to top 100% formulation weight. Formulation was finally mixeduntil homogeneity.

Example 13—Formulation of Encapsulated ATRA and Encapsulated BPO (E-ATRA0.1%/E-BPO 6%)

Ingredients:

-   -   (a) E-ATRA suspension: equivalent to 0.1% ATRA, (prepared        according to the procedure in Example 1).    -   (b) E-BPO suspension: equivalent to 6% BPO (prepared according        to the procedure in any one of Examples 2-11).    -   (c) Carbomer 980: 1.0% (Carbopol® 980 NF from Lubrizol)    -   (d) Hydroxyethyl cellulose: 0.7% (Natrosol® 250 HHX PHARM        hydroxyethylcellulose from Hercules).    -   (e) Sodium hydroxide (Sodium hydroxide pellets extra pure Ph        Eur, BP, JP, NF, FCC, E 524 from Merck)    -   (f) Water

Formulation Preparation:

Carbomer 980 & hydroxyethyl cellulose were dispersed in water to alump-free, homogeneous suspension. E-ATRA suspension was added intosuspension. E-BPO suspension was added into the suspension. Sodiumhydroxide was added to achieve pH values of 5.0±0.1. Water was added totop 100% formulation weight. Formulation was finally mixed untilhomogeneity.

Example 14—Formulation of Encapsulated ATRA and Encapsulated BPO (E-ATRA0.1%/E-BPO 6%)

Ingredients:

-   -   (a) E-ATRA suspension: equivalent to 0.1% ATRA, (prepared        according to the procedure in Example 1).    -   (b) E-BPO suspension: equivalent to 6% BPO (prepared according        to the procedure in any one of Examples 2-11).    -   (c) Hydroxyethyl cellulose: 1.25% (Natrosol® 250 HHX PHARM        hydroxyethylcellulose from Hercules).    -   (d) Hydroxypropyl cellulose: 0.5% (Natrosol® 250 HHX PHARM        hydroxyethylcellulose from Hercules).    -   (e) Glycerin: 15% (Glycerine 99.5% USP from Oleochemicals)    -   (f) Hydrochloric acid (Hydrochloric acid fuming 37% extra pure        Ph Eur, BP, JP, NF from Merck)    -   (g) Water

Formulation Preparation:

E-ATRA suspension was mixed with water. E-BPO suspension was added toE-ATRA suspension. Hydroxyethyl cellulose and hydroxypropyl cellulosewere wetted with glycerin in a separate container. The wetted paste wasadded to the E-ATRA and E-BPO suspension. Hydrochloric acid was added toachive a pH level of 3.5±0.1. Reminder of water was added to top upformulation to 100%. Formulation was finally mixed until homogeneity.

Example 15—Formulation of Encapsulated ATRA and Encapsulated BPO (E-ATRA0.1%/E-BPO 6%)

Ingredients:

-   -   (h) E-ATRA suspension: equivalent to 0.1% ATRA, (prepared        according to the procedure in Example 1).    -   (i) E-BPO suspension: equivalent to 6% BPO (prepared according        to the procedure in any one of Examples 2-11).    -   (j) Hydroxyethyl cellulose: 1.25% (Natrosol® 250 HHX PHARM        hydroxyethylcellulose from Hercules).    -   (k) Hydroxypropyl cellulose: 0.3% (Klucel®).    -   (l) Glycerin: 5% (Glycerine 99.5% USP from Oleochemicals)    -   (m) Hydrochloric acid (Hydrochloric acid fuming 37% extra pure        Ph Eur, BP, JP, NF from Merck)    -   (n) Water

Formulation Preparation:

E-ATRA suspension was mixed with water. E-BPO suspension was added toE-ATRA suspension. Hydroxyethyl cellulose and hydroxypropyl cellulosewere wetted with glycerin in a separate container. The wetted paste wasadded to the E-ATRA and E-BPO suspension. Hydrochloric acid was added toachive a pH level of 3.5±0.1. Reminder of water was added to top upformulation to 100%. Formulation was finally mixed until homogeneity.

Example 16—Stability of Formulations of Encapsulated ATRA andEncapsulated BPO (E-ATRA 0.1%/E-BPO 6%)

The following stability data was obtained from measurements offormulations of Examples 12-15 performed using Tretinoin assays weremeasured according to USP32, 2009 edition, page 3779—Tretinoin cream.

TABLE 1 Stability of Formulation in Example 12 Specification Zero TimeTests limits Time 2 w 1 month 2 month 3 month ATRA Assay 0.09-0.11%0.107 0.103 0.099 0.091 RSD, % LT 3.0% 0.8 0.8 0.2 0.9 Sum ofdegradation collect 0.42 0.83 1.22 1.47 products data degradation RRT0.25  0.34 0.23 0.22 0.19 products RRT 0.56  0.09 0.09 RRT 0.86  0.090.09 RRT 0.921 0.07 0.09 0.09 RRT 0.935 0.08 0.09 RRT 0.963 0.09 0.090.08 0.08 RRT 1.2  0.1 0.18 RRT 1.24  0.08 0.13 0.21 RRT 1.578 0.12 0.150.19 RRT 1.592 0.23 0.28 0.34

TABLE 2 Stability of Formulation in Example 13 Specification Zero TimeTests limits Time 8 days 1 month 2 month 3 month ATRA Assay 0.09-0.11%0.106 0.104 0.099 0.094 RSD, % LT 3.0% 0.6 0.8 0.3 0.1 Sum ofdegradation collect 0.51 1 1.57 1.91 products data degradation RRT 0.25 0.38 0.32 0.24 0.19 products RRT 0.28  RRT 0.56  RRT 0.86  0.09 RRT0.921 0.09 0.09 RRT 0.935 RRT 0.963 0.13 0.09 RRT 1.2  0.12 0.2 RRT1.24  0.11 0.23 0.36 RRT 1.578 0.2 0.24 0.29 RRT 1.592 0.46 0.66 0.77

TABLE 3 Stability of Formulation in Example 14 Specification Zero TimeTests limits Time 2 w 1 month 2 month 9 month ATRA Assay 0.09-0.11%0.107 0.102 0.1 RSD, % LT 3.0% 0.8 2.5 0.9 Sum of degradation collect0.44 0.6 0.7 products data degradation RRT 0.25  0.24 0.15 0.21 productsRRT 0.28  RRT 0.56  RRT 0.86  RRT 0.921 0.1 0.09 0.12 RRT 0.935 0.1 0.09RRT 0.963 RRT 1.2  RRT 1.24  RRT 1.578 0.11 0.16 RRT 1.592 0.18 0.24

TABLE 4 Stability of Formulation in Example 15 Specification Zero TimeTests limits Time 2 w 1 month 2 month 9 month ATRA Assay 0.09-0.11%0.109 0.107 0.105 0.104 RSD, % LT 3.0% 0.7 0.4 0.2 0.5 Sum ofdegradation collect 0.35 0.8 0.88 0.93 products data degradation RRT0.25  0.25 0.34 0.27 0.13 products RRT 0.28  RRT 0.56  RRT 0.86  0.08RRT 0.921 0.09 0.12 0.1 RRT 0.935 RRT 0.963 0.10 0.08 RRT 1.2  RRT 1.24 RRT 1.578 0.12 0.21 0.26 RRT 1.592 0.18 0.28 0.37

TABLE 5 Stability results of Formulations 12-15 (Zero time and 40 C.) 40C. Zero time 1 week % % % of degrad degrad degrad Formulation Assay RSDprod Assay RSD prod from t0 Example 12 0.107 0.8 0.42 0.092 1 1.88 14.0Example 13 0.106 0.6 0.51 0.09 0.2 2.8 15.1 Example 14 0.107 0.8 0.440.098 1.2 0.9 8.4 Example 15 0.109 0.7 0.35 0.104 0.9 0.7 4.6

TABLE 6 Stability Results of Formulations 12-15 (25 C.) 25 C. 2 weeks 1month 2 month % % of % % of % % of degrad degrad degrad degrad degraddegrad Formulation Assay RSD prod from t0 Assay RSD prod from t0 AssayRSD prod from t0 Example 12 0.103 0.8 0.83 3.7 0.099 0.2 1.22 7.5 0.0910.9 1.47 15.0 Example 13 0.104 0.8 1.0 1.9 0.099 0.3 1.57 6.6 0.094 0.11.91 11.3 Example 14 0.102 2.5 0.6 4.7 0.100 0.9 0.7 6.5 100.0 Example15 0.107 0.4 0.8 1.8 0.105 0.2 0.88 3.7 0.104 0.5 0.93 4.6

What is claimed is:
 1. Microcapsules comprising a core encapsulated by ametal oxide shell, wherein said core has a viscosity of between about300 cP to about 1,000,000 cP and comprises at least one active agent andat least one phase changing material; wherein the thickness of saidmetal oxide shell is in the range 0.1-10 micron; and wherein said shellis obtained from (a) metal oxide nanoparticles, and (b) a hydrolyzed andpolymerized sol gel precursor.
 2. The microcapsules according to claim1, wherein said at least one phase changing material is selected fromnatural or synthetic paraffin, aliphatic alcohols, fatty acids or anycombination thereof.
 3. The microcapsule according to claim 1, whereinsaid at least one active agent is selected form a pharmaceutical agent,a cosmetical agent and an agrochemical agent.
 4. The microcapsulesaccording to claim 1, wherein said core comprises a dermatologicalagent.
 5. The microcapsules of claim 1, wherein said core comprises adermatological agent selected from anti-fungal agents, anti-bacterialagents, anti-inflammatory agents, anti-pruritic agents, anti-psoriaticagent, anti-acne agents, anti-rosacea agents, and any combinationsthereof.
 6. The microcapsules of claim 5, wherein said anti-acne agentis selected from benzoyl peroxide, retinoid, and mixtures thereof. 7.The microcapsules according to claim 1, capable of being stable for aperiod of between about 2 weeks to about 2 years at room temperature. 8.A composition comprising microcapsules comprising a core encapsulated bya metal oxide shell, wherein said core has a viscosity of between about300 cP to about 1,000,000 cP and comprises at least one active agent andat least one phase changing material; wherein the thickness of saidmetal oxide shell is in the range 0.1-10 micron; and wherein said shellis obtained from (a) metal oxide nanoparticles, and (b) a hydrolyzed andpolymerized sol gel precursor.
 9. A method for treating a surfacecondition in a subject in need thereof, said method comprising topicallyadministering to said subject a composition according to claim
 8. 10.The method of claim 9, wherein said surface is skin or mucosal membrane.11. The method of claim 9, wherein said surface condition is a skindisease, disorder or condition selected from acne, infection,inflammation, pruritis, psoriasis, seborrhea, contact dermatitis,rosacea, and a combination thereof.